Implantable device

ABSTRACT

A device for implanting in the body. The device comprises a chamber containing cells. The device also comprises an oxygen generator for providing oxygen to the cells.

FIELD OF THE INVENTION

The present invention is in the field of devices implantable in a body,and more specifically to implanted devices containing living cells.

BACKGROUND OF THE INVENTION

Several disorders arising from hyposecretion of one or more substancessuch as hormones are known. Among these are diabetes, Parkinson'sdisease, Alzheimer's disease, hypo- and hyper-tension, hypothyroidism,and various liver disorders. The hormone insulin, for example, isproduced by β-cells in the islets of Langerhans of the pancreas. Innormal individuals, insulin release is regulated so as to maintain bloodglucose levels in the range of about 70 to 110 milligrams per deciliter.In diabetics, insulin is either not produced at all (Type 1 diabetes),or the body cells do not properly respond to the insulin that isproduced (Type 2 diabetes). The result is elevated glucose levels in theblood.

Disorders arising from hyposecretion of a hormone are usually treated byadministration of the missing hormone. However, despite advances inunderstanding and treating many of these diseases, it is often notpossible to precisely regulate metabolism with exogenous hormones. Adiabetic, for example, is required to make several daily measurements ofblood insulin and glucose levels and then inject an appropriate amountof insulin to bring the insulin and glucose levels to within theacceptable range.

Organ transplantation is not a viable treatment today for most of thesedisorders for several reasons including rejection of a transplantedorgan by the immune system. Isolated cells may be implanted in the bodyafter being treated to prevent rejection. e.g. by immunosuppression,radiation or encapsulation. Methods of immunoprotection of biologicalmaterials by encapsulation are disclosed in U.S. Pat. Nos. 4,352,883,5,427,935, 5,879,709, 5,902,745, and 5,912,005. The encapsulatingmaterial is selected so as to be biocompatible and to allow diffusion ofsmall molecules between the cells of the environment while shielding thecells from immunoglobulins and cells of the immune system. Encapsulatedβ-cells, for example, can be injected into a vein (in which case theywill eventually become lodged in the liver) or embedded under the skin,in the abdominal cavity, or in other locations. Fibrotic overgrowtharound the implanted cells, however, gradually impairs substanceexchange between the cells and their environment. Hypoxygenation of thecells ultimately leads to cell death.

U.S. Pat. No. 5,855,613 discloses embedding cells in a thin sheet ofalginate gel that is then implanted in a body.

U.S. Pat. No. 5,834,005 discloses immunoisolating cells by placing themin a chamber that is implanted inside the body. In the chamber, thecells are shielded from the immune system by means of a membranepermeable to small molecules such as glucose, oxygen, and the hormonesecreted by the cells, but impermeable to cells and antibodies. Theseimplanted chambers, however, do not have a sufficiently high surfacearea to volume ratio for adequate exchange between the cells and theblood. Thus, also in this case, hypoxygenation ultimately leads to celldeath.

SUMMARY OF THE INVENTION

The present invention provides an implantable device comprising achamber for holding functional cells and an oxygen generator forproviding oxygen to the cells within the chamber. The cells, referred toherein as “functional cells”, are loaded into the chamber of the devicethat is then implanted in the body. The device comprises an oxygengenerator. i.e. an element that can produce oxygen and make it availableto the cells, so that the functional cells do not suffer fromhypoxygenation. The oxygen generator thus produces oxygen and typicallyreleases the oxygen in the cell's vicinity.

The chamber has walls, which are permeable to nutrients needed by thecells as well as substances produced or secreted by the cells, suchsubstances including, for example, metabolites, waste products producedby the cells and substances needed by the individual produced by thefunctional cells. In the body, the functional cells are immunoisolatedfrom body constituents by the chamber's walls while being continuouslyexposed to adequate concentrations of oxygen, nutrients and hormoneswhich penetrate the chamber's walls. The fact that oxygen is supplied tothe cells by the oxygen generator allows the functional cells tomaintain a high metabolic rate, so that a smaller number of functionalcells are required for a given effect, as compared to prior art devices.The device containing the functional cells may be implanted in variousparts of the body such as under the skin or in the peritoneum. Thedevice may have any shape as required by a particular application. Inaccordance with one embodiment of the invention, the device isconfigured as a thin tubular element containing the functional cellwithin the tube's lumen. The device is typically of a size such that itmay be implanted by injection through an introducer such as a syringe.Such an implantation procedure may be short and last only about 10minutes. Other shapes of the device, e.g. a wafer shape, are alsocontemplated within the scope of the invention.

In one embodiment, the oxygen generator comprises photosynthetic cellsthat convert carbon dioxide to oxygen when illuminated. Thephotosynthetic cells are preferably unicellular algae, for example, ahigh temperature strain of Chlorella pyrenoidosa (cat. No. 1230. UTEX)having an optimal temperature about equal to body temperature. Otherphotosynthetic cells that may be used with the invention includeChlorella vulgaris, Scenedesmus obligus, Euglena, Volvox, and Spirolina.The photosynthetic cells may be autotrophic or mixotrophic. Isolatedchloroplasts may be used instead of, or in addition to, intact cells. Inthe case where the oxygen generator are photosynthetic cells the chambercomprises a light source, with an associated power source, such as abattery. The photosynthetic cells or chloroplasts may be containedwithin a separate compartment within the device, e.g. in the case of adevice in the form of a tube, they may be contained within a thinelongated chamber contained within the tube (in essence a smallerdiameter tube); or may be dispersed.

In another embodiment, the oxygen generator comprises a pair ofelectrodes. When an electric potential is applied across the electrodes,oxygen is released by electrolysis of ambient water molecules presentwithin the chamber. The electrodes are connected to a power source,typically a rechargeable battery.

The chamber may further comprise an oxygen sensor that determines theoxygen concentration in the vicinity of the functional cells. Amicroprocessor may be provided to turn the oxygen generator when thesensor detects that the oxygen concentration is below a predeterminedminimum and turns it off when the oxygen concentration is above apredetermined maximum.

The functional cells pancreatic islet cells (α-cells, β-cells, etc.),hepatic cells, neural cells, renal cortex cells, vascular endothelialcells, thyroid cells, parathyroid cells, adrenal cells, adrenal cells,thymic cells ovarian cells, and testicular cells. In accordance with onecurrently preferred embodiment the functional cells are pancreaticβ-cells, which are insulin-releasing cells. Such a device may beconfigured for use in the treatment of insulin-dependent diabetes or formonitoring glucose levels in the body. As another example, thefunctional cells may be hepatic cells, whereby the device can serve asan “artificial liver”.

The functional cell population in the device may be in the form ofindividual, may be in the form of cell clusters, or as pieces of excisedtissue. These tissues or cells include, without limitation, tissue orcells removed from a donor animal, tissue or cells obtained byincubation or cultivation of donor tissues and cells, cells obtainedfrom viable cell lines, cells obtained by genetic engineering. The cellsmay be of human or animal origin as well as genetically engineered orcloned cells or stem cells. The cells may be autologous or heterologouswith the recipient's cells. The tissues or cells may perform a usefulfunction by secreting a beneficial substance into the body, such ashormones or neurotransmitters, or removing a harmful substance from thebody by taking them up, such as in the case of hepatic cells which maytake up various toxic substances. The cells, cell clusters or tissuepieces may be dispersed in a liquid medium or matrix within the chamberor may be attached to a substrate, e.g. the walls of the chamber.

In another application, the chamber of the present invention is used toimplant cells in the body as part of a system for detecting ormonitoring the level of a substance in body fluids. Such a systemcomprises an implantable device of the invention having a detectoradapted to monitor a property of the functional cells that is correlatedwith the level of the substance in the medium surrounding the functionalcells. For example, U.S. Pat. No. 5,101,814, discloses use of a chamberfor implanting glucose sensitive cells into the body and monitoring anoptical or electrical property of the cells that is correlated withglucose levels. The present invention may incorporate a detectorarrangement of the kind disclosed in U.S. Pat. No. 5,101,814.

The present invention further concerns a method for treating anindividual suffering from a substance-deficiency by implanting in theindividual a device of the invention containing functional cells, whichcan secrete said substance. For example, if the individual suffers frominsulin-dependent (type I) the functional cells may be pancreaticβ-cells.

By another embodiment the method may employed for treating an individualsuffering from a condition where a beneficial effect may be achieved byremoval of a substance from the body, such as in cases of a livermal-function. The functional cells, in accordance with this embodimentare capable of removal of such substance.

The present invention further concerns a method of monitoring level of asubstance in an individual's body, comprising implanting the abovesystem in the individual's body and monitoring the reading of saiddetector.

The power source in the device of the invention is typically arechargeable battery. The device preferably comprises a rechargingcircuitry linked to said batter. For remote induction recharging of thebattery as known per se. The device preferably comprises also anelectronic circuitry for monitoring parameters of the device or itssurrounding or for controlling operational parameters of the device.Such monitored parameters may be parameters influencing the functionalcells' viability or the level of production of a needed substance e.g.the oxygen level; the level of a produced needed substance; the level inbody fluids of a substance which is to be produced or removed by thedevice; etc. The monitored parameters may, for example, be used in orderto control the level of oxygen production (by controlling the current tothe electrodes or the light generated by the light source, as the casemay be). The control circuitry may comprises means for wirelesscommunication with an external device, as known per se.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to understand the invention and to see how it may be carriedout in practice, preferred embodiments will now be described, by way ofnon-limiting examples only, with reference to the accompanying drawings,in which:

FIG. 1 is a device according to a first embodiment of the invention;

FIG. 2 is a device according to a second embodiment of the invention;

FIG. 3 is a device according to a third embodiment of the invention: and

FIG. 4 is a device according to a fourth embodiment of the invention.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS First Embodiment

Referring first to FIG. 1, an embodiment of the device of the invention,is shown in cross-sectional (FIG. 1 a) and longitudinal (FIG. 1 b) view.The device has a chamber 100 having the overall shape of a thincylinder. The chamber thus has an extremely large surface area to volumeratio allowing both efficient exchange of nutrients and waste and simpleinsertion and retrieval into and out of the peritoneum, or any otherbody area. The chamber 100 is flexible and may be made to assume anydesired configuration in the body.

Outer membrane 105 is formed from a semipermeable material, for example,a polyvinyl chloride acrylic copolymer. The molecular weight cut-off ofthe outer membrane 105 is selected so that the outer membrane 105 ispermeable to nutrients and active substances, such as hormones secretedby the cells but is impermeable to immunoglobulins and cells. Themolecular weight cutoff of the outer membrane 105 is preferably between10,000 and 70,000 Dalton. The outer membrane 105 has an anti-fibrincoating 145 that inhibits fibrotic overgrowth.

Inner membrane 110 is permeable to small inorganic molecules such asgases water and salts. The molecular weight cutoff of the inner membrane110 is preferably between 100 and 200 Dalton. The inner membrane 110 maybe made from materials commonly used for artificial lung membranes forexample, such materials as are disclosed in U.S. Pat. No. 5,614,378. Theinterior 130 of inner membrane 110 contains photosynthetic cells 135.The photosynthetic organisms may be, for example, unicellular algae suchas Chlorella. A light source 140 produces light preferably having awavelength in the range of 400 to 700 nm. Light is guided from the lightsource 140 along the length of the chamber 100 by an optic fiber 148.The chamber 100 contains a microprocessor 150, a power source 155 thatmay be for example, a rechargeable battery or any other kind of powersource, and an oxygen sensor 160. The photosynthetic cells 135constitute an oxygen generator.

Prior to implantation of the chamber 100 into the recipient's body,functional cells 120 are loaded into the annular space 115 between outermembrane 105 and inner membrane 110. The functional cells 120 may be,for example, pancreatic islets, in which case about 10⁶ islets aresufficient to produce adequate amounts of insulin to regulate glucoselevels in the recipient's body. The functional cells 120 may besuspended in a liquid medium in the annular space 115 or immobilized inthe annular space 115 by embedding in a gel matrix formed, for example,from alginate, polylysine, chitosan, polyvinyl alcohol, polyethyleneglycol, agarose, gelatin, or k-carrageenan.

After being loaded with the functional cells 120, the chamber 100 isimplanted into the body by means of an applicator that may be, forexample, a syringe. The processor 150, the light source 140 and thepower source 155 may also be implanted in the body, or may in use beexternal to the body. If the light source 140 in use is external to thebody, the optic fiber 148 is configured to pass through the skin. If theprocessor 150 in use is external to the body, the oxygen sensor 160 isconfigured to pass through the skin.

When oxygen sensor 160 detects that the oxygen level in the annularspace 115 is below a predetermined minimum, the light source 140 isturned oil by the microprocessor 150 in order to induce photosynthesisby the photosynthetic cells 135. The oxygen produced by photosynthesisin photosynthetic cells 135 is released from the photosynthetic cells135 and diffuses through the inner membrane 110 into the annular space115 and is thus made available to the functional cells 120. When oxygensensor 160 detects that the oxygen level in the annular space 115 isabove a predetermined maximum, the light source 140 is turned off by themicroprocessor 150 in order to stop photosynthesis by photosyntheticcells 135, so as to conserve the power source 155. About 10⁹-10¹⁰Chlorella cells are sufficient to produce an adequate supply of oxygenfor 10⁶ functional islets.

The power source 155 may periodically be recharged when the chamber 100is inside the body. For example, electrical contacts (not shown)normally located outside the body may be connected via a percutaneouscable to the terminals of the power source 155. An external voltage isthen applied across the contacts so as to recharge the power source 155.Alternatively, the power source 155 may be recharged inductively byapplying an electric field externally on the skin in the vicinity of thechamber 100.

Second Embodiment

Referring now to FIG. 2, a second embodiment of the invention, is shownin cross-sectional (FIG. 2 a) and longitudinal (FIG. 2 b) view. Thisembodiment is similar to the first embodiment shown in FIG. 1, andidentical components are identified by the same numeral. A pair offlexible electrodes 315 a and 315 b extends along the length of thechamber 300 in the interior 130 of the inner membrane 110. Theelectrodes are made of a biocompatible material such as carbon orplatinum. The chamber 300 contains a power source 355, a microprocessor350, and an oxygen sensor 160. The electrodes 315 a and 315 b constitutean oxygen generator.

Prior to insertion of the chamber 300 into the recipient's body,functional cells 120 are loaded into the annular space 115 between outermembrane 105 and inner membrane 110. The functional cells may besuspended in a liquid medium in the annular space 115 or immobilized byembedding the functional cells 120 in a gel matrix formed, for example,from alginate, polylysine, chitosan, polyvinyl alcohol, polyethyleneglycol, agarose, gelatin, or k-carrageenan.

The chamber 300 is then implanted in the body using an applicator thatmay be, for example, a syringe. The processor 350 and the power source355 may also be implanted in the body or may in use be external to thebody. If the processor 350 in use is external to the body, theelectrodes 315 a and 315 b and the oxygen sensor 160 are configured topass through the skin.

In the body, when oxygen sensor 160 detects that the oxygen level in theannular space 115 is below a predetermined minimum, the microprocessor350 causes an electric potential to be generated between the electrodes315 a and 315 b by means of the power source 355. This causes hydrolysisof water molecules in the interior 130 of inner membrane 110, producingoxygen. The oxygen molecules diffuse through inner membrane 110 into theannular space 115 between inner membrane 110 and outer membrane 105, andis thus made available to the functional cells 120. When the oxygensensor 160 detects that the oxygen level in the annular space 115 isabove a predetermined maximum, the electrical potential across theelectrodes 315 a and 315 b is turned off by microprocessor 350, so as toconserve the power source 155. The power source 155 may be rechargedwhen the chamber 300 is inside the body as described in reference to theprevious embodiment.

Third Embodiment

In FIG. 3, another embodiment of the invention is shown. This embodimenthas components in common with the embodiment of FIG. 1 and similarcomponents are identified with the same numeral. This embodiment has achamber 400 that is formed as a thin planar or wafer-like shape that isimplanted in the body close to the skin 402. The surface 405 of thechamber 400 closest to the skin 402 is transparent to light. Thephotosynthetic cells 135 and functional cells 120 are located in theinterior 410 of the chamber 400. The photosynthetic cells 135 areirradiated with light from a light source 415 located outside the body.Light from the light source 415 penetrates through the skin 402 and thesurface 405 to the interior 410 of the chamber 400. The processor 150and the power source 155 may also be implanted in the body or may in usebe located external to the body. The light source 415 may be integralwith the device as shown in FIG. 3 a. In this case when the oxygensensor 160 detects that the oxygen level in the interior 410 of thedevice 400 is below a predetermined minimum, the light source 415 isturned on by the processor 150 in order to induce photosynthesis of thephotosynthetic cells 135. When the oxygen sensor 160 detects that theoxygen level in the interior 410 is above a predetermined maximum, thelight source 415 is turned off by the processor 150.

The photosynthetic cells may also be illuminated by a light source 415that is independent of the processor 150 as shown in FIG. 3 b. In thiscase when the oxygen sensor 160 detects that the oxygen level in theinterior 410 of the device 400 is below a predetermined minimum, theprocessor 150 generates a sensible signal such as an audible signalproduced by a loudspeaker 450. This indicates to the individual that hemust irradiate the skin 402 overlying the chamber 400 in order to inducephotosynthesis of the photosynthetic cells 135. When the oxygen sensor160 detects that the oxygen level in the interior 410 is above apredetermined maximum, the processor 450 discontinues the sensiblesignal, thus informing the individual that the illumination should bestopped.

Fourth Embodiment

In FIG. 4, yet another embodiment of the invention is shown. Thisembodiment has components in common with the embodiment of FIG. 3 andsimilar components are identified with the same numeral. This embodimenthas a chamber 500 that is formed from a solid gel such as alginate,polylysine, chitosan, polyvinyl alcohol, polyethylene glycol, agarose,gelatin, or k-carrageenan. The gel is preferably transparent to light.The photosynthetic cells 135 and functional cells 120 are embedded inthe gel. The photosynthetic cells 135 are irradiated with light from alight source 415 located outside the body. Light from the light source415 penetrates through the skin 402 and the gel to the photosyntheticcells. The processor 150 and the power source 155 may also be implantedin the body or may in use be located external to the body. The lightsource 415 may be integral with the device as shown in FIG. 4 a. In thiscase when the oxygen sensor 160 detects that the oxygen level in theinterior 510 of the device 400 is below a predetermined minimum, thelight source 415 is turned on by the processor 150 in order to inducephotosynthesis of the photosynthetic cells 135. When the oxygen sensor160 detects that the oxygen level in the interior 510 is above apredetermined maximum, the light source 415 is turned off by theprocessor 150.

The photosynthetic cells may also be illuminated by a light source 415that is independent of the processor 150 as shown in FIG. 4 b. In thiscase when the oxygen sensor 160 detects that the oxygen level in theinterior 510 of the chamber 500 is below a predetermined minimum, theprocessor 150 generates a sensible signal such as an audible signalproduced by a loudspeaker 450. This indicates to the individual that hemust irradiate the skin 402 overlying the chamber 500 in order to inducephotosynthesis of the photosynthetic cells 135. When the oxygen sensor160 detects that the oxygen level in the interior 410 is above apredetermined maximum, the processor 150 discontinues the sensiblesignal thus informing the individual that the illumination should bestopped.

1. An implantable device comprising: a chamber holding isolated functional cells; and an oxygen generator for providing oxygen to the cells within the chamber, wherein the oxygen generator is disposed within the implantable device and comprises one or more photosynthetic units that produce oxygen when illuminated, the photosynthetic units positioned within the implantable device such that the oxygen produced is provided to the cells, and wherein the implantable device, as a whole, is implantable in the body of an individual.
 2. A device according to claim 1, further comprising an oxygen sensor for determining oxygen concentration in a vicinity of the functional cells.
 3. A device according to claim 2, further comprising a microprocessor configured to activate the oxygen generator when the oxygen concentration in the vicinity of the functional cells is below a first predetermined threshold, and to inactivate the oxygen generator when the oxygen concentration in the vicinity of the functional cells is above a second predetermined threshold.
 4. The device according to claim 2, further configured to produce a sensible signal when the oxygen concentration is below a predetermined value.
 5. A device according to claim 1, wherein the photosynthetic units comprise one or more photosynthetic cells.
 6. A device according to claim 5, wherein the photosynthetic cells are algae.
 7. A device according to claim 6, wherein the photosynthetic cells are unicellular algae.
 8. A device according to claim 7, wherein the unicellular algae are of the species Chlorella.
 9. A device according to claim 6, wherein the algae are genetically engineered algae.
 10. The device according to claim 5, further comprising a light source.
 11. The device according to claim 10, wherein the light source is configured to be implanted in the body.
 12. The device according to claim 10, wherein the light source is configured to be placed external to the body.
 13. The device according to claim 10, further comprising an optic fiber for conducting light from the light source to the photosynthetic cells.
 14. A device according to claim 1, wherein the photosynthetic units comprise isolated chloroplasts.
 15. The device according to claim 1, wherein the chamber has transparent walls.
 16. A device according to claim 1, wherein the functional cells release a needed substance and the chamber has walls, which are permeable to said substance but not to said cells, whereby said substance is released to the body.
 17. A device according to claim 16, wherein the functional cells are selected from the group consisting of: pancreatic islet cells, hepatocytes, thyroid cells, parathyroid cells, neural cells, ovarian cells, adrenal cells, renal cortex cells, vascular endothelial cells, thymic cells, ovarian cells, testicular cells, genetically engineered cells, cloned cells and stem cells.
 18. A device according to claim 1, wherein the functional cells can absorb or degrade a substance from the body, and the chamber has walls, which are permeable to said substance but not to said cells, whereby said substance is drained from surroundings of the device into said chamber.
 19. A device according to claim 1, comprising a rechargeable battery.
 20. A device according to claim 19, comprising an electric circuit linked to said rechargeable battery for remote induction recharging of said battery.
 21. A device according to claim 1, comprising an electronic circuitry for monitoring parameters of the device or its surrounding or controlling operational parameters of the device.
 22. A device according to claim 21, wherein said circuitry comprises means for wireless communication with an external control or monitoring circuitry.
 23. A device according to claim 1, wherein the functional cells comprise pancreatic β-cells.
 24. An implantable device for treating a medical disorder comprising a chamber, which is configured to be implanted in a body of an individual, the chamber holding: isolated functional cells that produce a substance for treatment of the medical disorder, the chamber having a wall that is permeable to the produced substance; and photosynthetic cells that convert carbon dioxide to oxygen when illuminated, wherein the device, when entirely implanted within the body, is configured such that the photosynthetic cells can be illuminated.
 25. The device according to claim 24, further comprising a light source.
 26. The device according to claim 25, wherein the light source is configured to be implanted in the body.
 27. A device according to claim 24, wherein the functional cells can release a needed substance, and the chamber has walls, which are permeable to said substance but not to said cells, whereby said substance is released to the body.
 28. A device according to claim 27, wherein the functional cells comprise pancreatic β-cells.
 29. A method of treating a medical disorder comprising: providing the device of claim 24; implanting the device in a body of an individual such that the photosynthetic cells can be illuminated; and when said device is implanted in the body, producing a treatment substance with said device and secreting said treatment substance to the body.
 30. A method according to claim 29, comprising illuminating the photosynthetic cells.
 31. A method according to claim 30, wherein illuminating the photosynthetic cells comprises illuminating the photosynthetic cells from within the body.
 32. An implantable device for treating a medical disorder comprising a chamber which is configured to be implanted in a body of an individual, the chamber holding: isolated functional cells that remove a substance from the body for treatment of the medical disorder, the chamber having a wall that is permeable to the substance; and photosynthetic cells that convert carbon dioxide to oxygen when illuminated, wherein the device, when entirely implanted within the body, is configured such that the photosynthetic cells can be illuminated.
 33. A method of treating a medical disorder comprising: providing the device of claim 32; implanting the device in a body of an individual such that the photosynthetic cells can be illuminated; and when said device is implanted in the body, removing a substance from the body with said device. 